Osteoporosis Clinical Trial
Official title:
Efficacy of a Calcimimetic (Cinacalcet) in the Long Term Control of Patients With Primary Hyperparathyroidism
To assess the efficacy and safety of treatment with cinacalcet and with cinacalcet plus alendronate in controlling bone loss induced by primary hyperparathyroidism.
The project was conducted at the Istituto Auxologico Italiano, IRCCS, Milano (Italy).
Principal Investigator: Maria Luisa Bianchi, M.D., Nephrologist, Bone Metabolism Unit,
Istituto Auxologico Italiano IRCCS, Milan, Italy
Other investigators:
Silvia Vai, M.D., endocrinologist, Bone Metabolism Unit, Istituto Auxologico Italiano IRCCS,
Milan, Italy Francesca Broggi, Dr., biologist, Bone Metabolism Unit, Istituto Auxologico
Italiano IRCCS, Milan, Italy Luca Persani, M.D., Endocrinologist, University of Milan &
Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan,
Italy
Introduction Cinacalcet is an orally active second-generation calcimimetic drug. Cinacalcet
increases the sensitivity of calcium receptors located on the surface of parathyroid cells,
thus inhibiting parathyroid hormone (PTH) secretion (which is increased in
hyperparathyroidism). Cinacalcet has been approved by FDA and EMEA for the use in dialyzed
patients affected by chronic renal failure with uncontrolled secondary hyperparathyroidism,
on the basis of three 6-month double-blind placebo-controlled studies on more than 1,100
patients.
PTH secretion and parathyroid cell proliferation are regulated by the serum levels of
ionized calcium (Ca++). The mechanism is based on the binding of the Ca++ ion to a G-protein
coupled membrane receptor (GPCR), called Calcium Sensing Receptor (CaR). With low
circulating levels of Ca++ or with an alteration of the calcium-receptor binding, higher
amounts of PTH are secreted, hyperparathyroidism develops, and in the long term systemic
alterations (bone mineral density (BMD) reduction, increased fracture risk, hypercalciuria,
renal stones, hypertension, etc.) appear.
Substances with calcimimetic action, such as Cinacalcet, have been recently developed. Until
now, Cinacalcet has been mainly used in hyperparathyroidism secondary to renal
insufficiency.
In this condition, Cinacalcet has been proven effective in reducing the circulating PTH to
acceptable levels, obtaining the normalization of serum Ca++ and phosphate levels in about
50% of cases. Moreover, the drug is usually well tolerated. Side effects (essentially nausea
and vomiting) are reported in about 30% of cases.
Pilot studies have confirmed the efficacy of Cinacalcet in maintaining a normal calcemia in
the long term also in patients with primary hyperparathyroidism (PHP) due to adenoma or
carcinoma of one parathyroid gland.
For this reason, the investigators proposed to use of Cinacalcet in cases of PHP, in which
surgical intervention was not possible, and its use in combination with oral alendronate in
the presence of osteopenia/osteoporosis.
Study objectives
- To assess the efficacy and safety of long-term Cinacalcet treatment in patients with
PHP, who are not operable, or in whom the localization of the parathyroid adenoma has
not been possible.
- To assess the efficacy of a combined therapy with Cinacalcet and alendronate in
controlling the bone loss induced by PHP.
Study design: prospective, single-arm, 24-month study, organized in two phases. During Phase
1, all patients were treated with Cinacalcet alone for 12 months. During Phase 2, all
patients were treated with Cinacalcet (as before) plus oral alendronate (70 mg once weekly)
for another 12 months.
The study was conducted in accordance with the Good Clinical Practice (GCP) rules, and was
approved by the Ethical Committee of the Istituto Auxologico Italiano, IRCCS.
Timelines
The study was organized as follows:
- 10 months for patient enrolment
- 24 months for the study (Phase 1 plus Phase 2)
- 6 months for the analysis of results
The enrolment was started after the approval of the protocol and the commitment of the
manufacturing Company to supply the Cinacalcet.
Study population 22 patients with PHP, who are not operable, or in whom the localization of
the parathyroid adenoma has not been possible, and with reduced bone density (T-score ≤ -2
at spine or hip) were included in the study. All patients were post-menopausal women.
Patients were included in the study, according to the pre-defined inclusion criteria (all 5
criteria must be met) and exclusion criteria (none of these criteria must be met).
Definition of PHP: serum intact PTH level higher than 65 ng/ml on at least two
determinations during the 12 months before the start of the study (after exclusion of severe
hypovitaminosis D), and serum calcium higher than 10.4 mg/dl.
All patients were studied in advance with parathyroid ecography or neck CT, and scintigraphy
with Sestamibi.
At the time of enrolment, the following exams were done:
1. evaluation of phosphate and calcium metabolism (blood: intact parathyroid hormone,
total calcium, ionized calcium, phosphate, creatinine, 25-hydroxy-vitamin D
1,25-dihydroxy-vitamin D, bone-specific alkaline phosphatase, C-terminal telopeptide;
urine: calciuria 24-hours, phosphaturia 24-hours, N-terminal telopeptide, creatinine
clearance)
2. bone density evaluation (DXA scan: radius, lumbar spine, proximal femur, and total
body)
3. general evaluation (liver function, blood cell count, renal function (serum creatinine
and creatinine clearance)
Treatment and follow-up The initial treatment regimen was 30 mg of Cinacalcet twice a day,
at 12-hour intervals.
The follow-up was done as follows:
- 2 weeks after starting Cinacalcet, the plasma levels of total calcium and intact PTH
were measured. If the calcemia was still above 10.6 mg/dl, the Cinacalcet dose was
doubled (60 mg twice a day).
- 4 weeks after starting Cinacalcet, the following biochemical parameters were measured:
blood: PTH, total calcium, ionized calcium, phosphate, creatinine, liver function,
blood cell count; urine: calciuria 24-hours, phosphaturia 24-hours, N-terminal
telopeptide, creatinine clearance. If calcemia was still above 10.6 mg/dl, the
Cinacalcet dose was increased 90 mg twice a day.
- every 8 weeks, the following biochemical parameters were measured: blood: PTH, calcium,
ionized calcium, phosphate, creatinine, liver function, blood cell count; urine:
calciuria 24-hours, phosphaturia 24-hours, N-terminal telopeptide, creatinine
clearance.
- after 12 months of Cinacalcet therapy, the DXA scan was repeated, and oral alendronate
at the dose of 70 mg weekly will be added
- at the end of the 24th month of therapy, all the exams done at the time of enrolment
were repeated During the study, if serum total calcium levels decreased below 8.4
mg/dl, the Cinacalcet daily dose was halved. If serum total calcium levels were still
below 8.4 mg/dl with the minimum dose of Cinacalcet (30 mg once a day), Cinacalcet was
stopped.
In these cases, serum calcemia was measured again at 1-week intervals, and the Cinacalcet
treatment was resumed accordingly.
All the patients' data were collected in a specially designed CRF (case report form).
Side effects and adverse reactions were appropriately recorded in the CRF. The severity of
the side effects or adverse reactions were evaluated in order to decide whether the involved
drug(s) should be stopped.
Adverse events (AE) were recorded in a dedicated section of the CRF, in accordance with the
standard rules of clinical trials. The adverse events were classified, as usual, as serious
AE (SAE) or non-serious AE (AE). For each AE severity and causality were recorded. SAEs were
immediately reported to the drug manufacturer (Amgen). Appropriate clinical decisions
(immediate and follow-up) were made.
According to the available literature, side effects of Cinacalcet were generally mild.
In case of severe side effects or SAE, treatment was to be stopped.
Methods All DXA scans and laboratory tests were performed at the Istituto Auxologico
Italiano IRCCS.
Bone mass was measured with a dual X-ray (DXA) Hologic Discovery densitometer at distal
radius, lumbar spine, hip and on total body.
Serum and urinary calcium and phosphorus were measured with standard methods. Serum bone
alkaline phosphatase (BSAP) were measured by EIA (enzyme-linked immunosorbent assay; Quidel,
San Diego, USA); serum C-terminal telopeptide (CTx) by immunoluminescent method (Roche
Diagnostic, Monza, Italy); urinary N-terminal telopeptide of procollagen type I (NTx) by EIA
(enzyme-linked immunosorbent assay; Ostex Intern. Inc., Seattle, USA). Serum intact
parathyroid hormone (PTH) was measured by immunoluminescent method (Roche Diagnostic, Monza,
Italy); 25-hydroxyvitamin D (25-OH D) by RIA (radioimmunological assay, DiaSorin Inc,
Stillwater, USA); 1,25-dihydroxyvitamin D (1,25(OH)2 D) by radio receptor assay (Nichols
Institute Diagnostics, San Juan Capistrano, USA).
Statistical methods
To evaluate the sample size, the following points were considered:
1. The study was focused on a well-characterized, homogeneous group of patients affected
by PHP without the possibility of surgical removal of the adenoma, and also affected by
osteopenia/osteoporosis.
2. These patients had already been followed at our Center for several years, so the risk
of drop-out re was very low (estimated 10%).
3. Considering the characteristics of the study (single-arm), a confidence level of 95%, a
5% significance, a drop-out rate of 10%, the 2.5% change in BMD, a sample size of 16
patients was calculated.
On the basis of the patients coming to our attention, the investigators estimated to be able
to enroll 20 patients meeting the inclusion criteria.
Data were expressed as the mean plus or minus SD. All the variables were analyzed to
evaluate their normality (Shapiro-Wilk test), in order to choose the appropriate statistical
tests.
To estimate the comparison of the means, after evaluating the validity assumptions, the
Student's t test and one-way ANOVA were used.
Statistical significance was defined as p<0.05, two-sided. At the end of the study, the
occurrence of adverse events was analyzed with descriptive statistics.
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Active, not recruiting |
NCT06287502 -
Efficacy of Structured Exercise-Nutritional Intervention on Sarcopenia in Patients With Osteoporosis
|
N/A | |
Completed |
NCT03822078 -
Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Denosumab (AMG 162) in Japanese Postmenopausal Women
|
Phase 1 | |
Recruiting |
NCT05845021 -
Surgeon-Initiated Bone Health Referral Pathway in Patients Undergoing Lower Extremity Arthroplasty
|
N/A | |
Completed |
NCT00092066 -
A Study to Evaluate the Safety, Tolerability, and Efficacy of an Investigational Drug and Dietary Supplement in Men and Postmenopausal Women With Osteoporosis (0217A-227)
|
Phase 3 | |
Recruiting |
NCT04754711 -
Interest of Nutritional Care of Children With Sickle Cell Disease on Bone Mineral Density and Body Composition
|
N/A | |
Completed |
NCT04736693 -
Replication of the HORIZON Pivotal Fracture Trial in Healthcare Claims Data
|
||
Not yet recruiting |
NCT06431867 -
Primary Care Management of Osteoporosis in Older Women
|
||
Completed |
NCT02922478 -
Role of Comorbidities in Chronic Heart Failure Study
|
||
Recruiting |
NCT02616627 -
Association Between DXA Results and the Complications, Clinical Courses and Outcomes in Chronic Dialysis Patients
|
||
Recruiting |
NCT02635022 -
Fragility Fracture Liaison Service and Anti-osteoporosis Medication Monitoring Service Study
|
||
Active, not recruiting |
NCT02617303 -
Prevention of Falls and Its Consequences in Elderly People
|
N/A | |
Completed |
NCT02566655 -
Clinical Trial of Intravenous Infusion of Fucosylated Bone Marrow Mesenchyme Cells in Patients With Osteoporosis
|
Phase 1 | |
Completed |
NCT03420716 -
Symbiotic Yogurt, Calcium Absorption and Bone Health in Young Adult Women
|
N/A | |
Completed |
NCT02559648 -
Denosumab vs Placebo in Patients With Thalassemia Major and Osteoporosis
|
Phase 2 | |
Not yet recruiting |
NCT02223572 -
Secondary Fracture Prevention in Patients Who Suffered From Osteoporotic Fracture
|
N/A | |
Completed |
NCT02003716 -
DeFRA Questionnaire as an Anamnestic Form
|
N/A | |
Unknown status |
NCT01913834 -
Nasally and sc Administered Teriparatide in Healthy Volunteers
|
Phase 1 | |
Not yet recruiting |
NCT01854086 -
Compliance and Persistence With Osteoporosis Treatment and Attitude Towards Future Therapy Among Post-menopausal Israeli Women During Drug Treatment or Drug Holiday
|
N/A | |
Completed |
NCT01401556 -
C-STOP Fracture Trial
|
N/A | |
Completed |
NCT02143674 -
Muscle Strengthening Exercises and Global Stretching in Elderly
|
N/A |